Triple-Negative Breast Cancers Challenge Researchers

New York(Dec 17, 2010)

Triple-negative cancers, a specific group of breast cancers that account for 10 to 20 percent of breast cancer cases, present a formidable challenge for doctors: they do not have readily identifiable characteristics to target. As a result, the cancers are unresponsive to commonly used drugs such as tamoxifen, anastrozole (Arimidex®), trastuzumab (Herceptin®), and lapatinib (Tykerb®) because they lack receptors for the hormones estrogen and progesterone and a protein called HER2 – identifiable targets that these drugs latch onto to destroy the cancer.

Triple-negative breast cancers are more common among African-American and Hispanic women – groups that comprise a large segment of the Hospital's breast cancer patients. They also tend to be aggressive, occur earlier in life, and are more likely to recur than other breast cancers.

"The only way we're going to make headway against these cancers and develop more effective treatments is to expand our understanding of the way they develop," said Ramon Parsons, M.D., Ph.D. Toward that goal, NewYork-Presbyterian Hospital researchers have been scrutinizing the biology of these cancers and participating in clinical trials to develop new treatment approaches.

About 90 percent of women with breast cancer who have alterations in a gene known as BRCA1 have triple-negative disease. In 1997, Dr. Parsons and his team identified a "tumor suppressor" gene called PTEN, and discovered that when BRCA1 is altered, PTEN loses its ability to put the brakes on cancer cell growth. "Once a cell loses PTEN, it has a growth advantage over its neighbors and starts on the road to cancer," Dr. Parsons explained.

Ramon Parsons, M.D.,Ph.D.

Dr. Parsons and his fellow investigators at NewYork-Presbyterian/Columbia University Medical Center are now studying an enzyme called PI3 kinase in a group of cancers called basal-like breast cancers, which account for most triple-negative tumors. "Since PI3 kinase is commonly mutated and PTEN is commonly inactivated in many breast cancers, we're seeking to develop a way to target this pathway with more effective therapies," said Dr. Parsons.

Because triple-negative breast cancer is actually a group of diseases with different biologies, no single therapy is likely to be effective for all women. Several clinical trials of new agents as well as combinations of existing agents are therefore underway.

For example, a phase I study at NewYork-Presbyterian/Columbia is evaluating the combination of three drugs: temsirolimus, erlotinib, and cisplatin. Cisplatin is a commonly used chemotherapy drug for breast cancer. Temsirolimus, which is used to treat advanced kidney cancer, targets a protein called mTOR, while erlotinib (used to treat lung and pancreatic cancers) homes in on a protein called the epidermal growth factor receptor. It is hoped that cisplatin could trigger cell death in cancer cells whose PI3 kinase survival pathways are inhibited by temsirolimus and erlotinib. The Principal Investigator of the study is Matthew Maurer, M.D.

Xin-Yun Huang, Ph.D.

Another promising group of drugs for women with triple-negative breast cancers includes PARP inhibitors. They are designed to inhibit "poly (ADP-ribose) polymerase," an enzyme which cancer cells use to repair the genetic damage caused by chemotherapy drugs. Through the New York Cancer Consortium, investigators at both NewYork-Presbyterian Hospital campuses are participating in a clinical trial assessing the PARP inhibitor veliparib with the drug doxorubicin. A second trial via the California Cancer Consortium is assessing veliparib with and without carboplatin in women with BRCA 1 and BRCA2 mutations and advanced breast cancers. A clinical trial at NewYork-Presbyterian/Weill Cornell Medical Center is evaluating the PARP inhibitor ABT-888.

Linda T. Vahdat, M.D.

In another NewYork-Presbyterian/Weill Cornell area of investigation, researchers led by Xin-Yun Huang, Ph.D., are studying synthetic versions (analogues) of migrastatin, a natural substance made by Streptomyces bacteria which inhibits the migration and invasion of metastatic breast cancer cells. They've shown that these migrastatin analogues inhibit a protein called fascin, which cancer cells use to support their internal structures. Fascin could potentially become a new molecular therapeutic target for triple-negative disease.

"We've seen the success that we've had in treating HER2-positive breast cancers with trastuzumab," said Linda Vahdat, M.D. "So a therapeutic approach targeting signaling pathways that drive triple-negative breast cancers also makes sense."

Contributing faculty for this article:

Ramon Parsons, M.D., Ph.D. is the Leader of the Breast Cancer Program at the Institute for Cancer Genetics at the Herbert Irving Comprehensive Cancer Center of NewYork-Presbyterian/Columbia University Medical Center. He is also the Avon Professor of Pathology and Medicine at Columbia University College of Physicians and Surgeons.